Are researchers fudging clinical trial statistics?

Before a clinical trial can commence a protocol – a plan of exactly how a trial will be conducted – will be formulated.  As part of the planning, the individuals undertaking the trial will calculate approximately how many patients need to take part for the results to be meaningful (the ‘sample size’) and prespecify which statistical tests they will perform on the data once the trial is complete.

A new study of published clinical trials, however, has found that many do not report these crucial sample-size calculations and that authors often do not mention if they have changed their mind as to which statistical test they are going to use.  About half of the trials studied by Chan et al. did not include sample-size calculations or mention whether the statistical tests actually used on the data differed from those provided in the trial protocol.

It is important that people conducting clinical trials stick to the statistical methods outlined in their protocol, as different types of statistical test can produce different outcomes for the same set of raw data.  If trial authors plan to use a particular test then change their mind and use a different test once they have seen the data, the results can be inadvertently biased – or directly manipulated – so they appear much more positive.

In the recent BMJ study, Chan et al. compared the published papers of 70 Danish randomized clinical trials with the corresponding protocols, which had been submitted to the local ethics committees for approval before the trials commenced.

Only 11 trials fully and consistently described sample-size calculations in both the protocol and the published paper. There were unacknowledged discrepancies between the calculations in the protocol and those in the published paper in 53% of cases.

Most protocols and publications specified which statistical tests would be used on the trial data; however, in 60-100% of cases the tests listed in the published paper differed from those in the protocol.

So it seems that in many cases sample size calculations and statistical methods are not prespecified in trial protocols or are poorly reported.  If they are prespecified, authors don’t tend to acknowledge instances when the statistical methods used differ from those in the protocol.  These two practices can easily introduce bias into the analysis of clinical trials and, ultimately, lead to misinterpretation of study results.

All this is bad news for everyone – if trial results aren’t reported honestly and transparently then it will be impossible to tell which trials, and therefore treatments, will genuinely help patients.  Hopefully initiatives such as SPIRIT (Standard Protocol Items for Randomised Trials), launched by Chan et al., and CONSORT (Consolidated Standards of Reporting Trials) will improve the accuracy of clinical trial reporting, but always remember: “There are three kinds of lies: lies, damned lies, and statistics”.

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Chan AW et al. (2008) Discrepancies in sample size calculations and data analyses reported in randomised trials: comparison of publications with protocols BMJ 337 (4 Dec 2008) DOI: 10.1136/bmj.a2299

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Welcome to the new look blog!

In sickness and in health has now moved from my old Blogger site to a spangly new WordPress site that forms part of my shiny personal website, www.helenjaques.co.uk.

The blog should work pretty much the same as the old site and the RSS feed is still the same, so all you need to do is update your favourites.  I hope you enjoy having a good rummage around, and please feel free to contact me if you have any comments or questions about the new blog or indeed the whole website.

On a similar note, I am also in the process of physically moving to France – I’ve been pretty busy undertaking this relocation so apologies that things have been a bit quiet on the blogging front.  Normal service will resume shortly…

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World AIDS Day roundup

Today December 1st is World AIDS Day. As many as 33 million people worldwide are living with HIV, and there are 80,000 people with HIV in the UK. The aim of World AIDS Day is to raise awareness of the challenges and consequences of the epidemic – ultimately halting the spread of the HIV virus and improving the lives of people living with infection.

The UK theme for World AIDS Day 2008 is “Respect & Protect“. Many people living with HIV face discrimination – this year’s campaign hopes to highlight the responsibility everyone has to transform attitudes to HIV and encourage actions that stop its spread. You can show your support for the campaign by wearing a red ribbon, which you can get your hands on in Gap, H&M, Selfridges and Levi’s stores around the UK, as well as in Red Cross charity shops.

There is a whole selection of events and promotions worldwide to mark World AIDS day. For example, this weekend a flash mob descended on Glasgow town centre, “freezing” while handing each another red ribbons and condoms in the event organized by the British Red Cross.

South Africa is poised to grind to a halt for 15 minutes to talk about AIDS. This weekend the country received £15 million worth of support from the UK to tackle the HIV epidemic. In South Africa, 20–30% of the population is HIV positive and as many as 365,000 people have died unnecessarily thanks to the AIDS denialism of former president Thabo Mbeki.

Online, AIDS.gov has launched the “Facing AIDS for World AIDS Day” campaign. Participants are invited to take a photo of themselves wearing a red ribbon and, on World AIDS Day, put the photo on their social networking site, blog, Twitter page, or website. There is also a Flickr group and a Facebook group where supporters can upload their pictures.

Digital magazine (RED)Wire by Product (RED), the charity run by Bono to engage the private sector in AIDS programmes, launched today. For a monthly subscription fee of £4, half of which will go to the Global Fund to help people in Africa with HIV and AIDS, users can get world premieres of exclusive tracks from the likes of Elton John, Jay-Z and Coldplay.

Bloggers Unite, a movement that aims to “harness the power of the blogosphere to make the world a better place”, has invited bloggers to dedicate their blog posts today to issues related to HIV/AIDS, with the aim of reminding people that HIV/AIDS is still a critical issue and to promote HIV testing. You can follow World AIDS day on Twitter with the tag #WAD08.

There is also a World AIDS day Musical Festival in Second Life, which will feature HIV/AIDS presentations and displays, tours, writing workshops, and virtual red ribbons and t-shirts.

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You’ve got mail… or chlamydia

The young people’s sexual health charity Brook has teamed up with the NHS and the laboratory testing company Preventx to offer free chlamydia testing kits through the post.

By using the Freetest.me website, young people between the ages of 16 and 24 can order a postal home testing kit, return their urine sample or vaginal swab by post, and receive the results by text message, email or on the website’s tracking service.

According to Brook, chlamydia is the most common sexually transmitted infection, with 1 in 10 people affected. Up to 75% of women and 50% of men with chlamydia have no symptoms, but left untreated the disease can cause serious health problems such as pelvic inflammatory disease and scarring of the reproductive system, and can lead to infertility.

Chlamydia can be treated easily with antibiotics, but these drugs can stop the contraceptive pill or patch from working.

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‘Two for the price of one’ tactic improves outcomes after organ transplantation

A new study of more than a million transplant recipients has found that rejection rates are lower in patients who receive two organs at once than in those who receive a single organ.

The study, published in Annals of Surgery, found that the rejection rates for organs cotransplanted with a donor-specific liver, heart or kidney were significantly lower than those for organs transplanted alone.

It has been known for some time that transplanting a liver with another organ such as a kidney or a section of intestine reduces the likelihood of rejection of the primary organ, leading to the suggestion that liver allografts protect other organs from rejection. Combined liver and kidney transplantation is used in patients with hepatorenal syndrome – in which acute kidney failure occurs as a result of liver cirrhosis or fulminant liver failure – or in patients with end-stage renal disease who also have liver damage as a result hepatitis B or C virus infection. Simultaneous intestine and liver transplantation is used in patients with intestinal failure following the removal of a large section of intestine (e.g. because of a tumor) and end-stage liver disease, which may be due to receiving their meals intravenously following intestine removal (total parenteral nutrition).

The recent study by Rana et al. has revealed that heart and kidney allografts are also immunoprotective and are themselves protected when transplanted with another organ.

The authors searched the United Network for Organ Sharing database – which contains data about every transplant that has taken place in the US since 1986 – and identified all thoracic, kidney, intestine and liver transplant recipients over 18 years old.

In patients who simultaneously received heart and kidney transplants from a single deceased donor, the incidences of renal allograft rejection and cardiac allograft rejection at one year were lower than in patients who received either a heart or a kidney allograft alone. In addition, the rate of rejection-free survival at one year was higher in the combined organ recipients. Likewise, compared with patients who received a single organ, rejection of either organ and rejection-free survival were lower and higher, respectively, in individuals who received combined liver and kidney transplants.

On the other hand, cotransplantation of intestine or pancreas in patients undergoing kidney or liver transplantation did not lower the risk of rejection or improve rejection-free survival.

The authors suggest that combined simultaneous organ transplantation could be used more widely to reduce rejection rates and lower the need for immunosuppression in transplant recipients.
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Rana A et al. (2008) The Combined Organ Effect: Protection Against Rejection? Annals of Surgery 248 (5): 871-879 DOI: 10.1097/SLA.0b013e31817fc2b8

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British Heart Foundation petition against cigarette machines

The British Heart Foundation has launched a petition to ban the sale of cigarettes from vending machines in the UK. The charity hopes that banishing cigarette vending machines will reduce the number of under 18s who take up smoking.

In the UK you need to be at least 18 years old to buy cigarettes from a shop and, technically, this old to get cigarettes from a vending machine. Vending machines aren’t manned, however, making it easier for under 18s to circumvent this rule and get their hands on cigarettes. 66% of adult smokers started when they were under age, so stopping people from taking up smoking as teenagers is crucial to prevent a livelong addition to cigarettes.

According to the BHF, 6% of children aged 11-15 are regular smokers and as many as one in six of these teenagers buy their cigarettes from cigarette vending machines. A 2007 study reporting on test purchases by young people found that teenagers were able to buy cigarettes from vending machines on more than four in ten occasions, with a number of councils reporting a 100% successful purchase rate. Using vending machines was the most successful way for young people to get hold of cigarettes – almost twice as successful as other ways tested such as purchasing cigarettes from a newsagent, off licence or petrol station kiosk.

Smoking is a leading risk factor for heart disease – of the 114,000 smokers who die as a result of smoking each year in the UK, one in four die from cardiovascular disease. Measures to help people quit smoking, or stop them from smoking in the first place, are thus a key part of the BHF’s strategy.

  • You can help put cigarette vending machines out of order for good by signing the BHF petition here.
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Chronic kidney disease patients claim to know nothing about their condition

A study by Finkelstein and colleagues published recently in Kidney International has found that as many of a third of patients with chronic kidney disease (CKD) claim to know nothing about their disease or about their treatment options when their kidneys ultimately fail.

CKD encompasses many types of kidney damage and is characterized by the gradual loss of renal function, often with few symptoms bar raised blood pressure and nonspecific signs such as fatigue and reduced appetite. CKD is graded on a 5-point scale, with stage 1 being slightly diminished kidney function and stage 5 being established kidney failure. Despite treatment many cases progress, in some instances to the point of kidney failure, otherwise known as end-stage renal disease. Once a patient reaches end-stage renal disease, they have to regularly undergo life-saving treatment that mimics the roles performed by their now defunct kidneys. Some such treatments include dialysis and kidney transplantation.

In the study by Finkelstein et al., 676 patients with stage 3–5 CKD who had been receiving nephrology care for about 5 years completed a questionnaire to assess their knowledge of CKD and of renal replacement therapies. Only 23% of patients reported having a great deal or extensive knowledge about their CKD and 35% reported having very limited or no knowledge. When questioned about their knowledge of renal replacement therapy, 35% of patients reported knowing nothing about any end-stage renal disease treatment modality.

Various studies have shown that decent education about CKD can delay the onset renal failure, increase the likelihood of the patient choosing a less costly home-based therapy rather than elaborate hospital-based dialysis, and improve outcomes of patients after the start of dialysis.

The findings of the Finkelstein et al. study indicate that despite receiving specialized kidney care for several years, many patients with CKD feel they have little knowledge of their disease and are, therefore, ill equipped to make treatment decisions. In an editorial accompanying the research, Chester Fox and Linda Kohn of University at Buffalo, New York, suggest that, “A multidisciplinary team – including dieticians, social workers, nurse educators, and pharmacists – and access to transplant surgeons are necessary to improve patient knowledge and understanding about progression of CKD and treatment options.”

Finkelstein FO et al. (2008). Perceived knowledge among patients cared for by nephrologists about chronic kidney disease and end-stage renal disease therapies Kidney International 74 (9): 1178-1184 DOI: 10.1038/ki.2008.376
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Another recent study, this time published in Archives of Internal Medicine, measured whether the introduction of early detection guidelines had improved the number of patients with CKD who were aware that they had the disease. The authors specifically asked 2,992 patients with stage 1-4 CKD whether or not they had been told that they had weak or failing kidneys. Between 1999 and 2004, awareness improved only in patients with stage 3 CKD. Patients with risk factors for CKD such as diabetes or hypertension were most likely to be aware of their disease.

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Testosterone skin patches improve sex drive in postmenopausal women

A considerable proportion of women – between 25% and 53% in fact – suffer from sexual problems, with libido taking a nosedive after the menopause as estrogen levels drop. Although low libido isn’t a health problem per se, it has been shown to have a negative effect on sexual relationships and overall wellbeing.

It has been known for several years that testosterone, administered as a skin patch, improves sexual function in postmenopausal women. Previous studies on sex drive in women have only looked at the effects of testosterone in females also taking estrogen therapy, as testosterone is thought to be ineffective without concurrent estrogen administration. Long-term estrogen therapy is, however, associated an increased risk of cardiovascular disease.

A recent study by Davis et al. has now shown that testosterone patches can improve libido in postmenopausal women taking no other hormone therapy. Sponsored by Procter & Gamble, the study found that use of the company’s Intrinsa testosterone patches doubled the number of satisfying sexual episodes a month in women with low libido.

The study – conducted at 65 centers in the US, Canada, Australia, the UK and Sweden – enrolled 814 women who had undergone natural or surgical (e.g. through hysterectomy) menopause and who were concerned about decreases in their levels of desire and sexual activity. These women were randomly assigned to receive daily placebo, 150 micrograms of testosterone a day or 300 micrograms of testosterone a day, which was administered via patches applied to the abdomen.

After 24 weeks of treatment, the increase in the number satisfying sexual episodes per month was greater in women receiving 300 micrograms of testosterone a day than in women receiving placebo (an increase of 2.1 episodes vs 0.7 episodes). The increase seen in women receiving 150 micrograms of testosterone a day, however, was not markedly greater than that in women on placebo (an increase of 1.2 vs 0.7 episodes). Both testosterone therapy groups showed a greater increase in sexual desire than the placebo group and a more notable decrease in libido-related personal distress.

The number of reported side effects throughout the 52-week study period was similar in all three groups, although there was a higher incidence of unwanted hair growth in the women receiving 300 micrograms of testosterone a day. Four women receiving testosterone were diagnosed with breast cancer compared with none in the placebo group, but at least one case was thought to have developed before the initiation of testosterone therapy and the other cases were put down to chance.

Speaking to CNN, Dr Sheryl Kingsberg, one of the coauthors of the study, said, “Although the change in activity is modest, that’s something that is appropriate and I think most women would be more than happy with it. They wanted to return to the level of desire they had in their premenopausal years, and that’s what they got.”

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Davis SR et al. for the APHRODITE Study Team (2008). Testosterone for Low Libido in Postmenopausal Women Not Taking Estrogen N Engl J Med 359 (19): 2005-2017 PMID: 18987368

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November 14th is World Diabetes Day

Tomorrow the International Diabetes Federation (IDF) is leading World Diabetes Day, the primary global awareness campaign of the diabetes world.

World Diabetes Day is celebrated annually November 14th, the birthday of Frederick Banting, who in 1922, along with Charles Best, conceived the idea that led to the discovery of insulin.

The theme for this year and for 2007 is ‘Diabetes in Children and Adolescents’. The incidence of type 1 diabetes in children is increasing at a rate of 3% each year and is increasing fastest in preschool children (a rate of 5% per year). Type 2 diabetes has been reported in children as young as 8 years old. Over half of all children with diabetes develop complications – such as heart disease and blindness – within 15 years.

The World Diabetes Day 2007-2008 campaign aims to:
• Increase the number of children supported by the IDF Life for Child Program, a international aid endeavor that provides life-saving medication to children with diabetes in developing countries.
• Raise awareness of the warning signs of diabetes.
• Encourage initiatives to reduce diabetic ketoacidosis.
• Promote healthy lifestyles to help prevent type 2 diabetes in children.

One of the key events of is the lighting of buildings and monuments in blue – the colour of the diabetes circle. In 2008, the aim is to encourage a total of 500 monuments and iconic buildings to light up to mark World Diabetes Day. The owners of the London Eye have already pledged to light up their monument; the Sears Tower in Chicago, Niagara Falls on the US/Canada border and the Alamo in Texas are also going blue. You can see pictures of buildings that were lit up in 2007 on the IDF Flickr page.

The global diabetes community is organizing a range of activities, including radio and television programmes, public information meetings, poster and leaflet campaigns, newspaper and magazine articles, events for kids, and walks, runs, and bicycle races.

Members of the public encouraged to show their support of diabetes awareness by lighting blue World Diabetes candles; a percentage of the sales of these candles will go to support children with diabetes on the Life for a Child Program.

The World Diabetes Day website includes lists of activities in various cities worldwide, so check it out and get involved!

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Cardiologists circumspect on stellar JUPITER results

The publication this week in New England Journal of Medicine of the JUPITER trial – which found that the statin rosuvastatin reduces the risk of heart attack and other cardiovascular events in people with normal cholesterol levels – has cause quite a stir. The likes of the BBC and the Daily Mail squealed that statins should be prescribed to all healthy adults, but what did the study actually look at, and what do doctors think of the findings?

In patients with raised cholesterol levels, treatment with statins reduces the risk of cardiovascular events such as heart attack and stroke; however, nearly half of all first cardiovascular events occur in people whose cholesterol levels are below current thresholds for pharmacological therapy. The JUPITER trial investigated the benefits of treatment with rosuvastatin (also known as crestor) in 17,802 patients over 50 years of age who had normal blood levels of low density lipoprotein (LDL) cholesterol (‘bad’ cholesterol), but elevated levels of another marker of heart disease called C-reactive protein (CRP).

Compared with a placebo, statin treatment reduced the levels of both LDL cholesterol and CRP by considerable amounts (50% and 37%, respectively), and also almost halved the likelihood of a major cardiovascular event such as a heart attack or stroke. When the results were broken down, it was found that the risk specifically of heart attack was reduced by 54% and the risk of fatal or nonfatal stroke decreased by 48%.

CRP levels are not usually measured in people at risk of heart disease, yet statin treatment had a remarkable effect in people who were otherwise apparently healthy but had elevated levels of this marker. Doctors are now been asking whether measurement of CRP levels should be undertaken in all people at risk of heart disease, and whether statins should be prescribed as a preventative measure to a wider range of people, regardless of whether their cholesterol levels indicate that they should receive such treatment.

In an editorial in the same issue of New England Journal of Medicine, Mark A Hlatky from Stanford University School of Medicine in California goes through the trial with a fine tooth comb to decide whether or not doctors should change how they prescribe statins.

He notes that “JUPITER was a trial of statin therapy, not high-sensitivity CRP testing”, and opines that “the evidence still favors [a] selective strategy for measuring high-sensitivity C-reactive protein, not routine measurement”. Dr Hlatky also points out that the trial was only 2 years long, so could not assess the effects of long-term statin treatment, and that the cost of rosuvastatin is much higher than that of generic statins, so the benefits of broader prescription of rosuvastatin treatment need to be weighed up against these factors.

You don’t have to just take Dr Hlatky’s word though. New England Journal of Medicine are hosting an online Clinical Directions poll to find out directly from doctors whether they are likely to change how they practice on the basis of the JUPITER results.

So far over 1,500 doctors and medical professionals have voted in the poll, and only 53% believe that the approach to laboratory screening and therapeutic use of statins in apparently healthy adults should be changed. The comments on the poll are just as cautious – Greg Rice of Libby, Montana says “Certainly what this study clearly shows most is that there is a large cohort of high risk patients we are missing. However, simply giving them a statin is not a very cost effective way to reduce the risk of coronary disease”, whereas Timur Timurkaynak of Ankara, Turkey states “I really wonder what have we learned from jupiter trial that we don’t know before”.

So it seems that the jury is going to being deliberating for some time as to whether apparently healthy people should have their CRP levels measured and should receive statins. The JUPITER trial seems to have thrown up more questions than it has answered, and it is clear that more research is needed before statins start getting dished out willy nilly.

  • Nature News has a good run down of the JUPITER study and whether you should be heading straight to your doctor for preventative statin treatment

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Ridker PM et al. (2008). Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein New England Journal of Medicine DOI: 10.1056/NEJMoa0807646

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